Substituted 4-aminoisoindoline-1,3-dione compounds and second active agents for combined use

Abstract

Provided herein are methods of using (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in combination with a second active agent for treating, preventing or managing hematological malignancies. The second active agent is one or more of an HDAC inhibitor, a BCL2 inhibitor, a BTK inhibitor, an mTOR inhibitor, a PI3K inhibitor, a PKCβ inhibitor, a SYK inhibitor, a JAK2 inhibitor, an Aurora kinase inhibitor, an EZH2 inhibitor, a BET inhibitor, a hypomethylating agent, a DOT1L inhibitor, a HAT inhibitor, a WDR5 inhibitor, a DNMT1 inhibitor, an LSD-1 inhibitor, a G9A inhibitor, a PRMT5 inhibitor, a BRD inhibitor, a SUV420H1/H2 inhibitor, a CARM1 inhibitor, a PLK1 inhibitor, an NEK2 inhibitor, an MEK inhibitor, a PHF19 inhibitor, a PIM inhibitor, an IGF-1R inhibitor, an XPO1 inhibitor, a BIRC5 inhibitor, or a chemotherapy.

What is claimed is: 
     
       1. A method of treating a hematological malignancy, comprising administering to a patient having the hematological malignancy a therapeutically effective amount of a compound in combination with a second active agent, wherein the compound is Compound 1: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; and wherein the second active agent is one or more of an HDAC inhibitor, a BTK inhibitor, an mTOR inhibitor, a PI3K inhibitor, a PKCβ inhibitor, a SYK inhibitor, a JAK2 inhibitor, an Aurora kinase inhibitor, a BET inhibitor, a hypomethylating agent, a DOT1L inhibitor, a HAT inhibitor, a WDR5 inhibitor, a DNMT1 inhibitor, an LSD-1 inhibitor, a G9A inhibitor, a PRMT5 inhibitor, a BRD inhibitor, a SUV420H1/H2 inhibitor, a CARM1 inhibitor, a PLK1 inhibitor, an NEK2 inhibitor, an MEK inhibitor, a PHF19 inhibitor, a PIM inhibitor, an IGF-1R inhibitor, an XPO1 inhibitor, or a BIRC5 inhibitor. 
     
     
       2. The method of  claim 1 , wherein
 the BTK inhibitor is ibrutinib, or acalabrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the mTOR inhibitor is rapamycin or an analog thereof (also termed rapalog); 
 the PI3K inhibitor is idelalisib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the PKCβ inhibitor is enzastaurin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the SYK inhibitor is fostamatinib, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the JAK2 inhibitor is fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the Aurora kinase inhibitor is alisertib, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the Aurora kinase inhibitor is barasertib, AZD1152-HQPA, danusertib, AT9283, PF-03814735, AMG900, tozasertib, ZM447439, MLN8054, hesperidin, SNS-314, PHA-680632, CYC116, GSK1070916, TAK-901, or CCT137690, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the hypomethylating agent is 5-azacytidine or decitabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the DOT1L inhibitor is SGC0946, or pinometostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the HAT inhibitor is C646, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the WDR5 inhibitor is OICR-9429, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the DNMT1 inhibitor is GSK3484862, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the LSD-1 inhibitor is 4-(2-(4-aminopiperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2-fluorobenzonitrile or seclidemstat, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the G9A inhibitor is UNC0631, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the PRMT5 inhibitor is GSK3326595, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the BRD inhibitor is LP99, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the BRD inhibitor is JQ1; 
 the SUV420H1/H2 inhibitor is A-196, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the CARM1 inhibitor is EZM2302, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the PLK1 inhibitor is BI2536, volasertib, CYC140, onvansertib, GSK461364, or TAK960, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the NEK2 inhibitor is JH-295 or rac-CCT 250863; 
 the PIM inhibitor is LGH-447, AZD1208, SGI-1776, or TP-3654, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; 
 the IGF-1R inhibitor is linsitinib; or 
 the BIRC5 inhibitor is YM155. 
 
     
     
       3. The method of  claim 1 , wherein the compound is a hydrochloride salt of Compound 1. 
     
     
       4. The method of  claim 1 , wherein the hematological malignancy is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin's lymphoma (HL), T-cell lymphoma (TCL), Burkitt lymphoma (BL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma (MZL), or myelodysplastic syndromes (MDS). 
     
     
       5. The method of  claim 4 , wherein the hematological malignancy is relapsed or refractory. 
     
     
       6. The method of  claim 4 , wherein the hematological malignancy is newly diagnosed. 
     
     
       7. The method of  claim 4 , wherein the hematological malignancy is DLBCL. 
     
     
       8. The method of  claim 7 , wherein the DLBCL is relapsed or refractory DLBCL. 
     
     
       9. The method of  claim 8 , wherein the DLBCL is refractory to one or more of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, bendamustine, lenalidomide, or gemcitabine. 
     
     
       10. The method of  claim 7 , wherein the DLBCL is newly diagnosed DLBCL. 
     
     
       11. The method of  claim 4 , wherein the hematological malignancy is CLL/SLL. 
     
     
       12. The method of  claim 11 , wherein the CLL/SLL is relapsed or refractory CLL/SLL. 
     
     
       13. The method of  claim 12 , wherein the CLL/SLL is relapsed or refractory to at least two prior therapies. 
     
     
       14. The method of  claim 13 , wherein at least one of the prior therapies is a Bruton's tyrosine kinase (BTK) inhibitor. 
     
     
       15. The method of  claim 14 , wherein the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or tirabrutinib. 
     
     
       16. The method of  claim 11 , wherein the CLL/SLL is newly diagnosed. 
     
     
       17. The method of  claim 4 , wherein the hematological malignancy is AML, and the AML is B-cell AML. 
     
     
       18. The method of  claim 4 , wherein the hematological malignancy is multiple myeloma, and the multiple myeloma is plasma cell leukemia (PCL). 
     
     
       19. The method of  claim 4 , wherein the hematological malignancy is TCL, and the TCL is anaplastic large cell lymphoma (ALCL) or Sezary Syndrome. 
     
     
       20. The method of  claim 4 , wherein the hematological malignancy is MZL, and the MZL is splenic marginal zone lymphoma (SMZL). 
     
     
       21. The method of  claim 1 , wherein the second active agent is an HDAC inhibitor. 
     
     
       22. The method of  claim 21 , wherein the HDAC inhibitor is panobinostat, romidepsin, or vorinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof. 
     
     
       23. The method of  claim 22 , wherein the HDAC inhibitor is panobinostat, panobinostat lactate, romidepsin, or vorinostat. 
     
     
       24. The method of  claim 21 , wherein the HDAC inhibitor is a HDAC6 inhibitor. 
     
     
       25. The method of  claim 24 , wherein the HDAC6 inhibitor is citarinostat, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof. 
     
     
       26. The method of  claim 25 , wherein the HDAC6 inhibitor is citarinostat. 
     
     
       27. The method of  claim 1 , wherein the second active agent is a BET inhibitor. 
     
     
       28. The method of  claim 27 , wherein the BET inhibitor is birabresib or 4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1 (2H)-one, BMS-986158, RO-6870810, CPI-0610, or molibresib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof. 
     
     
       29. The method of  claim 28 , wherein the BET inhibitor is birabresib or 4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1 (2H)-one. 
     
     
       30. The method of  claim 1 , wherein the second agent is an MEK inhibitor. 
     
     
       31. The method of  claim 30 , wherein the MEK inhibitor interrupts the function of the RAF/RAS/MEK signal transduction cascade. 
     
     
       32. The method of  claim 30 , wherein the MEK inhibitor is trametinib, trametinib dimethyl sulfoxide, cobimetinib, binimetinib, or selumetinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof. 
     
     
       33. The method of  claim 1 , wherein the second active agent is an XPO1 inhibitor. 
     
     
       34. The method of  claim 33 , wherein the XPO1 inhibitor is selinexor.